Atorvastatin is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. Atorvastatin is useful for example as the calcium salt, i.e. [R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The molecular weight of atorvastatin calcium is 1209.42. Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile, slightly soluble in ethanol, and freely soluble in methanol. However, atorvastatin is also useful as the magnesium salt. The atorvastatin salts may be either in crystalline form or in amorphous form or in a mixture of crystalline and amorphous form.
Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is said to be similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is said to be the same regardless of the time of day of drug administration
It is well-known that statins are pharmacologically active in the hydroxy acid form, whereas the corresponding lactone form may be considered a pro-drug which may convert to the active hydroxy acid in vivo. Atorvastatin is conveniently applied in drug composition as a salt of the pharmacologically active hydroxy acid form.
The atorvastatin hydroxy acid form-lactone form equilibrium and inter-conversion kinetics is pH highly dependent. The acid-catalyzed reaction is reversible, whereas the base-catalyzed reaction is practically irreversible: At pH>6, the equilibrium reaction is not detectable and greatly favors the hydroxy acid form (Kearney et al., Pharmaceutical Research, 1993, vol. 10, no. 10, p. 1461-65).
Accordingly, it is advisable to establish a near-neutral or basic microenvironment for atorvastatin in the pharmaceutical composition in order to stabilize the equilibrium, i.e. avoid presence of the inactive lactone form, for example a micro-environment having a pH above about 5 or even a pH above about 6.
WO 2006/123358 discloses a pharmaceutical composition comprising atorvastatin and a carrier comprising about 0.5% to about 3.0% by weight of tromethamine and an additional stabilizer such as an antioxidant.
U.S. Pat. No. 6,126,971 disclose the use of a pharmaceutically acceptable inorganic alkalizing compound as a stabilizer in a pharmaceutical composition comprising atorvastatin. Such inorganic alkalizing compounds are typically conventional basic salts of metals or alkaline earth metals. Typically, calcium carbonate is used for this purpose. However, in order to achieve the desired effect, a considerable amount of calcium carbonate is necessary, typically from about 5% w/w to about 75% w/w.
Such a high amount of calcium carbonate in a pharmaceutical composition creates vast problems in preparing tablets (solid dosage forms).
Accordingly, there is an unmet need for a stable atorvastatin-containing composition which can easily be processed into tablets.